Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

Dorard C, de Thonel A, Collura A, Marisa L, Svrcek M, Lagrange A, et al. Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis. Nat Med 2011;17:1283–9.Microsatellite instability (MSI) has been well described in colorectal cancer. Microsatellite repeat sequences, which exist throughout the genome, become unstable due to defective mismatch repair, leading to somatic mutations in microsatellite sequences, some of which are oncogenic. To identify new oncogenic mutations in MSI colorectal cancers, Dorard and colleagues analyzed expression patterns of 45 candidate genes located downstream of introns containing repeat sequences in the vicinity of splice acceptor sites. Two exons generated a novel reverse-transcriptase PCR product specifically in tumors containing microsatellite repeats. One of these, MRE11, had been previously described; however, the second corresponded to a mutant version of heat shock protein HSP110. The mutant HSP110 protein, missing exon 9, was expressed in all MSI colorectal cell lines and primary tumors examined, and in just over half of MSI adenomas. The mutant HSP110 was impaired in its normal chaperone and antiapoptotic functions, acting as a dominant negative to wild-type HSP110. Colorectal cancers arising through MSI tend to be sensitive to chemotherapy and show an improved prognosis. Overexpression of the mutant HSP110 protein further sensitized colorectal cancer cells to chemotherapy, with high levels of the mutant HSP110 mRNA correlating with improved survival. These data suggest that HSP110 modulates both prognosis and response to therapy in MSI colorectal cancer and provide insights into its mechanism of action.Liu P, Cheng H, Santiago S, Raeder M, Zhang F, Isabella A, et al. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat Med 2011;17:1116–20.Phosphoinositide 3-kinase (PI3K) is frequently activated in human malignancies. To study the mechanisms of possible resistance to therapies targeting PI3K, Liu and colleagues generated a conditional transgenic mouse model of PI3K-induced breast cancer. They found that, upon suppression of a mutant allele, many tumors reoccurred. Genomic analyses of these tumors surprisingly revealed evidence for amplification of Met or Myc. Interestingly, tumors that had activated Met were still dependent, whereas tumors that had activated Myc were independent of PI3K. Thus, Myc activation appears to be an important potential mechanism of resistance to targeted inactivation of PI3K. These results dramatically illustrate the importance of Myc activation in the maintenance of a neoplastic phenotype in PI3K-driven tumorigenesis.Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J Exp Med 2011;208:2005–16.A major obstacle in tumor immunotherapy is achieving a protective antitumor response, likely due to the fact that tumorspecific T-cell responses are lacking. However, recent data from human studies, primarily in melanoma, have revealed that spontaneous T-cell responses against tumor antigens can be found in cancer patients. A recent report by Fuertes and colleagues revealed high frequencies of CD8+ T cells specific for MelanA/MART-1, MAGE-10, and NY-Eso-1 in the blood of patients with metastatic melanoma. To understand the nature of innate immune cell signals mediating this sterile inflammatory response to tumors, the authors conducted gene expression analysis of human melanoma metastases and found a positive correlation between several T-cell markers and IFN-induced transcripts IRF1 and p30. This observation prompted an in vivo mechanistic investigation in a mouse model of transplantable tumor to determine whether host type I IFN signals were necessary for spontaneous priming of CD8+ T cells against tumor antigens. Analysis of IFN-α/βR−/− and IFN-α/βR−/−/IFN-γR−/− mice revealed that type I IFNs indeed are critical mediators for generation of spontaneous antitumor CD8+ T cells. Using an elegant analysis of bone marrow chimeric mice, the authors revealed that host type I IFN signaling through Stat1 is required for optimal generation of tumor antigen-specific CD8+ T cells. In addition, using Batf3−/− mice, Fuertes and colleagues demonstrated that the CD8a+ dendritic cell subpopulation is critical for spontaneous priming of tumor antigen-specific CD8+ T cells, and that these lie downstream of host type I IFN signaling. It was further revealed in the chimeric bone marrow mice that, through type I IFN signaling in CD8α+ dendritic cells, optimal priming of tumor antigen-specific CD8+ T cells occurs. This compelling study supports the possibility for intratumoral delivery of type I IFNs, which are currently approved by the U.S. Food and Drug Administration, for promoting activation in tumor antigen-specific CD8+ T cells, and the potential mobilization of immune responses that support tumor rejection.Roodhart JM, Daenen LG, Stigter EC, Prins HJ, Gerrits J, Houthuijzen JM, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 2011;20:370–83.Disseminated cancers often have a transient response to chemotherapy. However, chemoresistance is not solely a property of the malignant cells. Other cells in the tumor microenvironment also can make a major contribution. Roodhart and colleagues describe a rapidly induced environmental-resistance mediated by local mesenchymal stem cells, (MSC), revealing an interesting mechanism of action with important clinical implications. The hypothesis addressed in the study was that MSCs could confer resistance to chemotherapy. MSCs are multipotent cells capable of differentiating into adipocytes, fibroblasts, and perivascular and vascular structures in tissue repair, wound healing, and inflammation; thus, it comes as no surprise that these cells are recruited in large numbers into tumor microenvironments. In mouse modeling experiments, i.v. injection of as few as 50,000 MSCs abolished the antitumor effects of cisplatin chemotherapy. Even more remarkable was the fact that as small an amount as 1,000 MSCs injected into the opposite flank of a tumor-bearing mouse could mediate resistance, indicating a systemic mechanism of action. Conditioned medium from cisplatin-treated MSCs (but not those treated with 5-fluorouracil or irinotecan) induced in vitro and in vivo resistance to chemotherapy. Having eliminated various obvious explanations, the authors used metabolomics to identify 2 distinct platinum-induced polyunsaturated fatty acids (PIFA) that, in minute quantities, induce resistance to a broad spectrum of chemotherapies. Moreover, blocking enzymes involved in production of these PIFAs (cylcooxygenase-1 and thromboxane synthase) prevented MSC-induced chemoresistance. Is this relevant to patients with disseminated cancer? Certainly circulating human MSCs can be found in sufficient numbers to generate a similar response to platinum, as human MSCs have similar actions on cisplatin-treated human tumor xenografts in immune-deficient mice and PIFAs were found in plasma from cisplatin-treated patients. Importantly, PIFAs are also found in various food products and “health” supplements, such as fish oils and algae extracts, which are often used by cancer patients. Oral administration of purified PIFAs, fish oils, or algae extracts at doses similar to those used by humans induced platinum-resistance in tumor-bearing mice. Thus, at least 2 potentially important clinical implications can be drawn from the results of this study: Food supplements containing PIFAs should be avoided during chemotherapy, and inhibitors of the enzymes that produce PIFAs may enhance the actions of chemotherapy.Janssen A, van der Burg M, Szuhai K, Kops GJ, Medema RH. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 2011;333:1895–8.Tumors frequently exhibit abnormal numbers of chromosomes (aneuploidy), as well as changes in chromosome structure, such as deletions and/or translocations. Errors in chromosomal segregation during mitosis can clearly influence the ploidy of tumor cells; however, can this phenomenon also contribute to abnormalities in chromosomal structure? To address this question, Janssen and colleagues induced erroneous kinetochore-microtubule attachments with the use of Monastrol and examined chromosomal segregation in vitro, following release from Monastrol block. Chromosomal segregation abnormalities were observed in the majority of cells and were also associated with DNA damage. Interestingly, markers of DNA damage were typically restricted to DNA positioned at or near the cleavage furrow between dividing cells, indicating that DNA damage occurred as a consequence of chromosomes being trapped in the furrow and becoming damaged during cytokinesis. Consistent with these observations, daughter cells inheriting broken chromosomes contained foci of double-strand breaks, activating p-ATM, p-Chk2, and p-p53. Damaged chromosomal foci produced as a result of segregation errors typically disappeared after 8 hours. The authors went on to reveal that damaged chromosomes were repaired through nonhomologous end joining of broken chromosomes, resulting in chromosomal translocations. Thus, chromosomal segregation errors, known to result in aneuploidy, can also induce chromosomal translocations in daughter cells. In cancers that show frequent chromosomal instability, such instability results in both aneuploidy and structural chromosomal aberrations, both of which contribute to malignant progression.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.